Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

10 May 2024 | Contributor(s): Silva-Brenes, Diana V., Reyes-Vargas, Stephanie K., Duconge, Jorge, Vlaar, Cornelis, Stelzer, Torsten, Monbaliu, Jean-Christophe M.

While racemic warfarin was initially commercialized as a rodenticide, it has become the most prescribed anticoagulant drug for prevention of blood clots and is part of the World Health Organization’s list of essential medicines. The synthesis of warfarin appears straightforward, consisting of a...

Rapid production of the anaesthetic mepivacaine through continuous, portable technology

24 Apr 2024 | Contributor(s): Díaz-Kruik, Pablo, Paradisi, Francesca

Local anaesthetics such as mepivacaine are key molecules in the medical sector, so ensuring their supply chain is crucial for every health care system. Rapid production of mepivacaine from readily available commercial reagents and (non-dry) solvents under safe conditions using portable,...

Multi-step Flow Synthesis of the Anthelmintic Drug Praziquantel

24 Apr 2024 | Contributor(s): Phull, Manjinder Singh, Bohara, Chander Singh, Gundla, Rambabu, Mainkar, Prathama S., Jadav, Surender Singh

Praziquantel (PZQ; Brand name: Biltricide) is categorized as an anthelminthic drug, and it is used for the treatment of Schistosomiasis and other parasitic infections. The World Health Organization (WHO) has classified it as one of the essential and emergency medicines needed across the globe....

Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 2: Cyclization, Chlorination, and Amination

24 Apr 2024 | Contributor(s): Prieschl, Michael, Sagmeister, Peter, Moessner, Christian, Sedelmeier, Joerg, Williams, Jason D., Kappe, C. Oliver

A new route to the cannabinoid receptor type 2 agonist, RG7774, has been developed circumventing an alkylation with poor regioselectivity as the final step. In the new synthetic route, this side chain is incorporated from the beginning. In this article, the development of the final four...

A Continuous Process for Manufacturing Apremilast. Part I: Process Development and Intensification by Utilizing Flow Chemistry Principles

24 Apr 2024 | Contributor(s): Hsieh, Hsiao-Wu, Griffin, Daniel J., Ananthoji, Padmini, Avci, Nadide Hazal, Brown, Derek B., Ericson, Ari, Fostinis, James D., Irfan, Muhammad, Langille, Neil, Lovette, Michael A., Murray, James I., Spada, Simone, Thiel, Oliver R., Aiello, Frankie, Daou, Joseph, Goudas-Salomon, Nicole, Pan, Ende, Sarkar, Nandini, Wimalasinghe, Rasangi, Wu, Zufan Steven, Zeng, Alicia, Beaver, Matthew G., Cohen, Carolyn M.

Herein, we report the development of an integrated continuous manufacturing (CM) process for the penultimate step in the synthesis of apremilast, the drug substance (DS) of the commercial product Otezla. This development effort was motivated by the desire to create an alternative manufacturing...

The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing Organizations

09 Jun 2023 | Contributor(s): McWilliams, JC, Allian, ADOpalka, SM, May, SA, Journet, M, Braden, TM

This manuscript provides the results of an in-depth survey assessment of the capabilities, experience, and perspectives on continuous processing in the pharmaceutical sector, with respondents from both pharmaceutical companies and Contract Manufacturing Organizations (CMOs). The survey includes...

Small-Volume Continuous Manufacturing of Merestinib. Part 1. Process Development and Demonstration

09 Jun 2023 | Contributor(s): Cole, KP, Reizman, BJHess, M, Groh, JM, Laurila, ME, Cope, RF, Campbell, BM, Forst, MB, Burt, JL, Maloney, TD, Johnson, MD, Mitchell, D, Polster, CS, Mitra, AW, Boukerche, M, Conder, EW, Braden, TM, Miller, RD, Heller, MR, Phillips, JL, Howell, JR

Development of a small volume continuous process that used a combination of batch and flow unit operations to manufacture the small molecule oncolytic candidate merestinib is described. Continuous processing was enabled following the identification and development of suitable chemical...

Small-Volume Continuous Manufacturing of Merestinib. Part 2.Technology Transfer and cGMP Manufacturing

09 Jun 2023 | Contributor(s): Reizman, Brandon J., Hess, Molly, Burt, Justin L., Maloney, Todd D., Johnson, Martin D., Laurila, Michael E., Cope, Richard F., Luciani, Carla V., Buser, Jonas Y., Campbell, Bradley M., Forst, Mindy B., Mitchell, David, Braden, Timothy M., Lippelt, Christopher K., Boukerche, Moussa, Starkey, Derek R., Miller, Richard D., Chen, Jing, Sun, Baoquan, Kwok, Martin, Zhang, Xin, Tadayon, Sam, Huang, Ping

Technology transfer of a small volume continuous (SVC) process and Current Good Manufacturing Practices (cGMP) manufacturing of merestinib are described. A hybrid batch-SVC campaign was completed at a contract manufacturing organization under cGMP. The decision process by which unit operations...

Separation and Purification in the Continuous Synthesis of Fine Chemicals and Pharmaceuticals

09 Jun 2023 | Contributor(s): O'Mahony, M, Ferguson, SStelzer, T, Myerson, A

The use to both chemists and chemical engineers working in flow synthesis, this chapter provides a summary of separation and purification operations that can be applied to flow synthesis reaction streams. Both single and biphasic separations for the liquid phase are detailed. Separation and...

Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and sustainable Fine-Chemical Manufacturing

09 Jun 2023 | Contributor(s): Morin, Mathieu, Zhang, Wenyao, Mallik, Debasis, Organ, Michael G

Process analytical technology (PAT) is a system designed to help chemists better understand and control manufacturing processes. PAT systems operate through the combination of analytical devices, reactor control elements, and mathematical models to ensure the quality of the final product through...

Scaling continuous API synthesis from milligram to kilogram: extending the enabling benefits of micro to the plant

09 Jun 2023 | Contributor(s): Berton, M, de, Souza, JMAbdiaj, I, McQuade, DT, Snead, DR

The signature benefits of continuous flow are largely a result of a reactor's micro-sized features. However, as the technology gains industrial traction in the synthesis of active pharmaceutical ingredients (API), the reactors must be scaled to larger size to meet production demands. Often, the...

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

09 Jun 2023 | Contributor(s): Hu, Chuntian

Pharmaceutical production remains one of the last industries that predominantly uses batch processes, which are inefficient and can cause drug shortages due to the long lead times or quality defects. Consequently, pharmaceutical companies are transitioning away from outdated batch lines, in large...

PAT Implementation on a Mobile Continuous Pharmaceutical Manufacturing System: Real-Time Process Monitoring with In-Line FTIR and Raman Spectroscopy

09 Jun 2023 | Contributor(s): Miyai, Yuma, Formosa, Anna, Armstrong, Cameron, Marquardt, Brian, Rogers, Luke, Roper, Thomas

The strategies and experimental methods for implementation of process analytical technology (PAT) on the mobile pharmaceutical manufacturing system, Pharmacy on Demand (PoD), are discussed. With multiple processes to be monitored on the PoD end-to-end continuous manufacturing process, PAT and its...

On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Development of a Highly Efficient Synthesis for Ciprofloxacin

09 Jun 2023 | Contributor(s): Armstrong, Cameron, Miyai, Yuma, Formosa, Anna, Thomas Dale, Chen, Esther, Hart, Travis, Schultz, Victor, Desai, Bimbisar, Cai, Angela, Almasy, Alexandra, Jensen, Klavs, Roper, Thomas

The experimental approach taken and challenges overcome in developing a high-purity production (>100 g) scale process for the telescoped synthesis of the antibiotic ciprofloxacin is outlined. The process was first optimized for each step sequentially with regard to purity and yield, with...

Model-based comparison of batch and flow syntheses of an active pharmaceutical ingredient using heterogeneous hydrogenation

09 Jun 2023 | Contributor(s): Kim, J, Yonekura, HWatanabe, T, Yoshikawa, S, Nakanishi, H, Badr, S, Sugiyama, H

This work presents a model-based comparison of the batch and flow syntheses for doripenem, which is an antibiotic active pharmaceutical ingredient. The targeted reaction is heterogeneous hydrogenation, the most widely used method for reduction reaction in drug syntheses. We developed rigorous...

Integrated Flow Processing - Challenges in Continuous Multistep Synthesis

09 Jun 2023 | Contributor(s): Pieber, B, Gilmore, K, Seeberger, PH

The way organic multistep synthesis is performed is changing due to the adoption of flow chemical techniques, which has enabled the development of improved methods to make complex molecules. The modular nature of the technique provides not only access to target molecules via linear flow...

Implementing Continuous Manufacturing for the Final Methylation Step in the AMG 397 Process to Deliver Key Quality Attributes

09 Jun 2023 | Contributor(s): Tom, JK, Achmatowicz, MMBeaver, MG, Colyer, J, Ericson, A, Hwang, TL, Jiao, N, Langille, NF, Liu, M, Lovette, MA, Sangodkar, RP, Kumar, SS, Spada, S, Perera, D, Sheeran, J, Campbell, K, Doherty, T, Ford, DD, Fang, YQ, Rossi, E, Santoni, G, Cui, S, Walker, SD

In this article, we describe the process development efforts to improve the final methylation step in the AMG 397 drug substance process, culminating in the execution of a Good Manufacturing Practice (GMP) continuous manufacturing process. During the development, batch kinetic studies and...

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

09 Jun 2023 | Contributor(s): Yu, E, Mangunuru, HPRTelang, NS, Kong, CJ, Verghese, J, Gilliland, SE, Ahmad, S, Dominey, RN, Gupton, BF

Numerous synthetic methods for the continuous preparation of fine chemicals and active pharmaceutical ingredients (API's) have been reported in recent years resulting in a dramatic improvement in process efficiencies. Herein we report a highly efficient continuous synthesis of the antimalarial...

Flow Chemistry, Continuous Processing, and Continuous Manufacturing: A Pharmaceutical Perspective

09 Jun 2023 | Contributor(s): May, SA

Flow chemistry has become a vibrant area for Research Article over the past decade. This perspective is intended to capture insights on how these advances have and will continue to impact the development and commercialization of active pharmaceutical ingredients. A series of chemistry examples...

Continuous-Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

09 Jun 2023 | Contributor(s): Gutmann, B, Cantillo, D, Kappe, CO

In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in organic synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of...

Continuous Production of Five Active Pharmaceutical Ingredients in Flexible Plug-and-Play Modules: A Demonstration Campaign

09 Jun 2023 | Contributor(s): Rogers, L, Briggs, NAchermann, R, Adamo, A, Azad, M, Brancazio, D, Capellades, G, Hammersmith, G, Hart, T, Imbrogno, J, Kelly, LP, Liang, GH, Neurohr, C, Rapp, K, Russell, MG, Salz, C, Thomas, DA, Weimann, L, Jamison, TF, Myerson, AS, Jensen, KF

Traditional pharmaceutical manufacturing is based on a complex supply chain that is vulnerable to spikes in demand and interruptions. Continuous pharmaceutical production in compact modules is a potential solution that allows for drug manufacturing when and where it is needed with significantly...

Continuous manufacturing of drug substance and small molecules: process and equipment view

09 Jun 2023 | Contributor(s): Yazdanpanah, Nima

The continuous manufacturing of pharmaceutical compounds and fine chemicals is in high interest for the industry due to significant technical, quality, and economical advantages. This manufacturing method has its own challenges. Beside the more efficient, safer, and greener synthesis rout, a new...

Continuous Flow C-Glycosylation via Metal-Halogen Exchange: Process Understanding and Improvements toward Efficient Manufacturing of Remdesivir

09 Jun 2023 | Contributor(s): von;Keutz, T, Williams, JD, Kappe, CO

As remdesivir is the first approved treatment for COVID-19 (SARS-CoV-2), its production is likely to be of vital importance in the near future. Continuous flow processing has been demonstrated as a key technology in the manufacturing of highvolume active pharmaceutical ingredients and is...

Continuous flow technology vs. the batch-by-batch approach to produce pharmaceutical compounds

09 Jun 2023 | Contributor(s): Cole, KP, Johnson, MD

Introduction: For the manufacture of small molecule drugs, many pharmaceutical innovator companies have recently invested in continuous processing, which can offer significant technical and economic advantages over traditional batch methodology. This Expert Review will describe the reasons for...

Continuous end-to-end production of solid drug dosage forms: Coupling flow synthesis and formulation by electrospinning

09 Jun 2023 | Contributor(s): Balogh, Attila, Domokos, András, Farkas, Balázs, Farkas, Attila, Rapi, Zsolt, Kiss, Domokos, Nyiri, Zoltán, Eke, Zsuzsanna, Szarka, Györgyi, Örkényi, Róbert, Mátravölgyi, Béla, Faigl, Ferenc

Based on the concept of continuous manufacturing an end-to-end benchtop device was developed unprecedented for the production of solid drug dosage forms by connecting flow synthesis and formulation via electrospinning (ES). Together with the optimized two-step continuous-flow synthesis of...